Practical Use of Anticoagulants July 13, 2009 Henry Green, MD, FACC, FACP

HEPARINS Heparins are thrombin-inhibiting drugs. They act by forming a complex with antithrombin, which is more effective than antithrombin itself in inactivating thrombin and factor Xa. They are relatively ineffective against fibrin-bound thrombin. Complications of heparin include bleeding, osteoporosis, skin necrosis, hypersensitivity reactions, and heparininduced thrombocytopenia. Heparin rebound In patients with acute coronary syndromes, ischemia may recur after discontinuation of heparin. There is increased incidence of death or myocardial infarction in the ensuing 12 hours. This seems to be more likely when the infusion is continued for a prolonged period, and possibly with a higher peak aPTT. The mechanism may be increased platelet activation and aggregation. This can be offset by administration of eptifibatide. This effect appears to be less with the use of enoxaparin.20 Unfractionated heparin This is usually given intravenously. The dose-response curve varies considerably among patients, and the amount given must be adjusted to the activated partial thromboplastin time. The therapeutic range is usually considered to be 1.5 to 2.5 times the control, but this may be subtherapeutic. A common loading dose is 5000 u or 80 u/kg, followed by a continuous infusion of 18 u/kg/hr. Its onset of action is immediate when given intravenously. Its half-life is about 90 minutes, but varies widely with the amount administered. It can prolong the prothrombin time. The initial APTT should be obtained 6 hours after starting the drug, and should be repeated several times in the first 24 hours. Platelet counts are recommended at base line and daily thereafter. In the case of patients with ST-elevation myocardial infarction who are receiving thrombolytic therapy, a loading dose of 60 u/kg (maximum 4000 u) is recommended, followed by 12 u/kg/hr (maximum 1000 u).21 The prophylactic dose of unfractionated heparin is 5000 u subcutaneously every 8 hours. Protamine sulfate reverses heparin. The dose is 1 mg for every 100 u of heparin remaining in the patient. Protamine is also an anticoagulant and can worsen bleeding if given in excessive doses. It may also cause anaphylaxis. Low molecular weight heparins These drugs catalyze antithrombin. They inhibit factor Xa more than they inhibit thrombin itself. They generally have a predictable dose-response curve. They are given subcutaneously, in a weight-adjusted dose, and do not require monitoring except in special cases (pregnancy, renal dysfunction, very obese patients (> 150 kg) or very small ones (< 40 kg)). Monitoring is done by measuring anti-activated factor X activity. They are contraindicated in patients with severe renal failure. These drugs should not be given to patients receiving an epidural or spinal anesthetic, because of the risk of spinal epidural hematoma.

1

Enoxaparin (Lovenox) is given subcutaneously, either as 1 mg/kg every 12 hours or 1.5 mg/kg once daily (maximum 180 mg daily). 40 mg. once daily is used for prophylaxis against thrombosis. For patients undergoing thrombolytic therapy for an ST-elevation myocardial infarction, an iv dose of 30 mg is given initially, followed in 15 minutes by 1 mg/kg every 12 hours, provided the patient is less than 75 years old. Older patients are not given the loading dose, and the maintenance dose is 0.75 mg/kg every 12 hours.21 Patients who are to receive angioplasty are given a bolus of 0.3 mg/kg intravenously, if they have not received the drug subcutaneously for at least 8 hours. Otherwise no bolus is given.21 Dalteparin (Fragmin) is given subcutaneously either as 100 units/kg every 12 hours, or 200 units/kg once daily (maximum 18,000 units daily). Fondaparinux (Arixtra) This is a synthetic heparin analog that inhibits activated factor Xa. It is given subcutaneously once daily. The dose for thrombophlebitis or pulmonary embolism is usually 7.5 mg daily. For patients weighing less than 50 kg it is 5 mg and for those over 100 kg, it is 10 mg. Peak action is in 2 hours. Its half-life is 17 to 21 hours. It is cleared renally, and its half-life is prolonged in renal failure. It does not affect the prothrombin time, APTT, bleeding time or platelet function. It is also very effective for thromboembolic protection. The dose for this purpose is 2.5 mg once daily. Patients receiving thrombolytic therapy may be given an initial dose of 2.5 mg intravenously, followed by 2.5 mg subcutaneously once daily.21 It should not be used if the creatinine clearance is under 30 ml/min, if platelet count is under 100,000, or in patients weighing less than 50 kg that have undergone hip or knee replacement. There is increased bleeding risk if the patient is receiving an anti-inflammatory drug. It is not bound to platelet factor IV. However, the package insert carries a warning to be cautious in patients with history of HIT syndrome. Heparin-induced thrombocytopenia (HIT syndrome)7 Type I This is a mild thrombocytopenia. It develops in 10-20% of patients on heparin within the first 3 days of therapy. It does not result in thrombosis, and resolves spontaneously without stopping heparin. Type II This develops in 1-3% of patients that are on unfractionated heparin. It occurs in 0.5% of those treated with low molecular weight heparin. It is an immune-mediated syndrome resulting from formation of an antibody to platelet factor 4-heparin complex. This complex activates platelets, and results in arterial and venous thrombosis. In spite of the drop in platelets, the risk of thrombosis is much greater than that of bleeding. This may take the form of stroke, myocardial infarction, major arterial thrombosis, pulmonary embolism, deep vein thrombosis, etc. At 30 days, without specific treatment, the risk of thrombosis is 53%. HIT type II usually develops 4 to 5 days after starting heparin. It may occur earlier than four days in patients that have received heparin within the previous several weeks. Sometimes it begins one to two weeks after stopping heparin. Criteria for diagnosis consist of a drop in platelet count to under 100,000, or a drop of 50% in

2

the count from base line, in the absence of other reasons for thrombocytopenia. Several laboratory tests are available to detect anti-platelet factor 4. Do not delay treatment while awaiting confirmatory laboratory tests. All forms of heparin should be stopped immediately, and a direct thrombin inhibitor substituted. The two approved choices are lepirudin and argatroban. Warfarin is contraindicated until the acute phase has resolved, as it increases the risk of thrombosis. PROPHYLAXIS FOR THROMBOEMBOLISM This should be strongly considered in hospitalized patients who are at risk for venous thrombosis. An example would be a patient over the age of 40 who is likely to be immobilized for 3 days or more. Other significant risk factors include: acute infections acute respiratory disease inflammatory bowel disease previous thromboembolism thrombophilia estrogen therapy

congestive heart failure stroke advanced age immobility varicose veins cancer

acute myocardial infarction arthritis recent surgery or trauma obesity central venous catheterization

Any of the regimens cited above is acceptable However if the patient is at risk of bleeding, then graded compression stockings or pneumatic compression devices are acceptable alternatives. WARFARIN A vitamin K antagonist, it limits hepatic production of factors II, VII, IX and X. It also interferes with production of protein C and S, which are natural anticoagulants. It is available in the following tablet strengths: 1, 2, 2.5, 5, 7.5 and 10 mg. Initiating and maintaining therapy Older patients, thin patients, and patients in congestive heart failure may be more sensitive to warfarin. This is also true of patients taking certain medications that interact with it (see below). We no longer use a loading dose of warfarin. Keep in mind that a change in dosage does not fully take effect for considerably more than 24 hours. Most patients are started at 5 mg. daily. One algorithm is as follows:1

3

Day 1 2 3

4

5

6

INR

Warfarin dose, mg 5 5 <1.5 10 1.5-1.9 5 2-3 2.5 >3 0 <1.5 10 1.5-1.9 7.5 2-3 5 >3 0 <2 10 2-3 5 >3 0 <1.5 12.5 1.5-1.9 10 2-3 7.5 >3 0

A pharmacogenomics approach for initiating warfarin has also been proposed. If warfarin is being used for an acute event, such as deep vein thrombosis, heparin or enoxaparin should be started concomitantly and continued for at least five days. The time to peak antithrombotic effect of warfarin is at least four days, regardless of the INR. The INR should be in the therapeutic range for at least two days. On the other hand, if warfarin is being used solely for prophylaxis (e.g. in atrial fibrillation without embolism), it can be started as an outpatient without heparin. Cleveland Clinic approach: Check INR daily or every other day until in therapeutic range for two days Then every 3 to 5 days When stable for 1 week, check INR weekly If stable for another 2 to 3 weeks, increase interval to 4 weeks. Patients with protein C or S deficiency should be started on heparin if they need warfarin, and the warfarin is initiated in low dose (e.g. 2 mg daily), since there is an initial fall in protein C when warfarin therapy is begun. Once the patient is on a fairly stable program, most physicians make minor adjustments in total weekly dose by small increments or decrements of the dose on specific days of the week. For example if the patient has been on 5 mg daily (35 mg per week) and the INR needs to be lowered slightly, the patient may be instructed to take half a tablet every Wednesday and Sunday, a total of 30 mg per week. Intensity of therapy For most indications, INR should be 2-3. For mechanical heart valves in mitral position, 2.5-3.5 is appropriate. If the patient experiences a thromboembolic event while on warfarin, it may be necessary to use a higher target INR. 4

Duration of therapy Permanent Prothrombotic states Mechanical prosthetic valves Atrial fibrillation Deep vein thrombosis or pulmonary embolism when the predisposing cause is irreversible Thrombotic event in patients with cancer that cannot be resolved Limited – identifiable and reversible cause (surgery, pregnancy, trauma, immobilization, etc) Pulmonary embolism or proximal venous thrombosis with identifiable cause – minimum 3 months (6 months may be better) Ventricular thrombus – 6 months Following orthopedic procedures -- weeks Proximal vein thrombosis without identifiable cause ≥ 6 months Bioprosthetic valves – 3 months It has been proposed that a followup positive d-dimer test may be an indication to extend the duration of anticoagulation. Contraindications to warfarin: Noncompliance Older people who are at high risk of falling Patients at high risk of bleeding Warfarin complications Bleeding Bleeding is the most common complication. Minor bleeding is common. The incidence of serious bleeding (intracranial or requiring transfusion or fatal) ranges from under 1% to as high as 7% in various series. On average, the risk of major bleeding is about 3% per year with an annual case fatality rate of 0.6%.4 Bleeding is more frequent in older patients, and in those with anemia, diabetes, history of GI bleeding, stroke or recent myocardial infarction. Administration of aspirin or nonsteroidal anti-inflammatory drugs can also be ulcerogenic, contributing to the possibility of gastrointestinal bleeding. Skin necrosis This usually occurs in patients with protein C or S deficiency. It is rare, and tends to occur between the third and eighth day of therapy. Atheroembolism The purple toes syndrome refers to a painful mottled or purplish discoloration of the toes. It may appear about three to eight weeks after starting warfarin. The color blanches with pressure or elevation of the leg. Necrosis and amputation may result, but the lesions can be reversible. The syndrome is believed to be a manifestation of athereroembolism, which could be enhanced by the use of warfarin. Other atheroembolic phenomena, such as livedo reticularios, abdominal pain, hematuria, renal failure, hypertension, or stroke are also reported.

5

Special situations Unexpected change in INR – suspect the following: Lab error New medications Dosing error – missed doses or extra doses Wrong strength tablets Dietary changes, alcohol Medical problems (heart failure, diarrhea, thyroid disorders) Bleeding Major bleeding is managed according to the algorithm in the next section. Minor bleeding should not be ignored. It can indicate that the INR is too high, and should alert the patient and physician to repeat the test. The finding of blood in the urine or in the stool may be due to a malignancy or other significant disorder of the urinary tract or gut. It should not be attributed to the anticoagulant alone, as the circulation is a closed system. From time to time such a finding can lead to the discovery of an otherwise occult lesion, sometimes malignant.. Overdose management 1. INR 3.3-4.9 without significant bleeding: Lower the dose, or omit a dose and restart at lower dose 2. INR 2-4.9 a. Urgent reversal for invasive procedure: hold warfarin and give 1.25-5 mg of vitamin K PO, depending on amount of reversal needed. b. Emergency reversal for surgery: hold warfarin and give 1-5 mg vitamin K IVPB over 30 minutes 3. INR 5-8.9 without significant bleeding a. If no additional risk factors for bleeding, omit 1 or 2 doses of warfarin and restart at a reduced dose when INR is in therapeutic range. b. If other risk factors for bleeding (e.g. peptic ulcer or recent surgery) omit next dose of warfarin and give vitamin K 1.25-2.5 mg PO. Restart warfarin when INR in therapeutic range. c. If urgent surgery needed, give 2.5-5 mg vitamin K PO, expecting that INR will decrease within 24 hours. 4. INR 9-20 without significant bleeding, give 2.5-5 mg. vitamin K PO, expecting INR to decrease rapidly within 12-24 hours. Monitor INR closely and repeat vitamin K if necessary. 5. INR > 20 or any INR requiring rapid reversal (serious bleeding or life-threatening event) Give vitamin K 10 mg IVPB over 30 minutes along with fresh frozen plasma. May repeat vitamin K every 12 hours. Avoid SQ vitamin K since effect is delayed and unpredictable. The drug should be given orally (1.25-2.5 mg) or IVPB diluted to 50 ml and given over 30 minutes. Do not give it by IV push. Anticoagulation during pregnancy A common situation is that of a young patient with a mechanical prosthetic heart valve. Warfarin can cause an embryopathy, characterized by CNS abnormalities and fetal bleeding when given during the first trimester. There are three options for managing the pregnant patient: 1. Give warfarin throughout pregnancy, risking embryopathy. This maximizes maternal protection.

6

2. Give enoxaparin throughout pregnancy. This is controversial. If it is used, one must monitor the antifactor-Xa levels (both peak and trough) frequently. Target is a level of 0.5 to 1 u/ml 4 to 6 hours after a dose. 3. Give unfractionated heparin during the first trimester, and then warfarin until about 38 weeks, and switch back to heparin, inducing labor at about 40 weeks. Heparin is given subcutaneously every 12 hours at 35,000 u daily. It should be monitored at least twice weekly. Higher heparin requirements occur in the third trimester. Warfarin does not preclude the mother from nursing her child Warfarin and surgery The decision as to whether to “bridge” the patient with heparin is an important one. The mortality of valve thrombosis is 15%., and embolic stroke has a 70% risk of death or major neurologic deficit. 1. Low risk procedures do not necessarily require withholding warfarin. Examples include cataract surgery and most dental and dermatologic procedures. Complex dental extractions or more invasive dental procedures do require holding warfarin. 2.

Some procedures are safe when the INR is ≤ 1.5, e.g. colonoscopy, sigmoidoscopy or upper endoscopy, even with biopsy. However some consider polypectomy a significant bleeding risk, especially with large sessile polyps. Higher risk procedures include polypectomy, esophageal dilatation or placement of a PEG catheter.

3.

Many operations carry a high risk of bleeding. These include major orthopedic surgery, cardiac surgery, urologic surgery, neurosurgery, major vascular operations, prostate and kidney surgery, and implantation of devices, such as pacemakers and defibrillators.

4.

If warfarin needs to be stopped, usually it is safe to do so 5 days before the procedure, but one should always check the INR on the day of the operation.

5.

Emergency surgery requires rapid reversal of warfarin. This can be done with fresh frozen plasma. This carries the same risk as other transfusions, and it is not long lasting. It does not confer warfarin resistance.

6. Vitamin K works more slowly and also may make it difficult to get the patient back into the therapeutic range afterward. It can take 24 to 96 hours to work. To avoid warfarin resistance, use small doses of vitamin K (1 to 2.5 mg). A 5 to 10 mg dose works faster, but increases the difficulty of getting the patient’s INR back to a therapeutic level. 7.

“Bridging” with heparin is necessary for patients who are at high risk for thromboembolism while warfarin is being held.3 High-risk patients: Deficiency of protein C or S or antithromin III Antiphospholipid antibody syndrome Homozygous factor V Leyden mutation Recurrent arterial or venous thrombembolic event Recent arterial or venous thrombosis (< 3 mos)

7

Atrial fibrillation (high-risk category) Acute intracardiac thrombus Mechanical cardiac valve Bioprosthetic cardiac valve less than 3 months old, or in a patient with atrial fibrillation Intermediate risk patients (decide on case by case basis whether to bridge) Recurrent stroke or TIA Newer mechanical valves (St Jude, e.g.) Prosthetic aortic valve Atrial fibrillation without history of embolism but with risk factors for embolism Venous thrombosis >3-6 mos ago Low risk (no bridging) Remote venous thrombosis (>6 mos ago) Cerebrovascular disease without stroke or TIA Atrial fibrillation without risk factors Newer prosthetic valve in aortic position Bridging with unfractionated heparin requires hospitalization. Enoxaparin (Lovenox) can be given as an outpatient. Warfarin is stopped 5-6 days prior to surgery (i.e. hold 4-5 doses). Enoxaparin is started 36 hours after the last dose. The last dose of low molecular weight heparin should be a half-dose, given 24 hours before surgery. 24 hours after surgery, it is usually safe to restart enoxaparin and warfarin, but hemostasis should be reassessed beforehand. Should postoperative bleeding occur, it is likely to delay warfarin therapy for up to a week or more. Continue enoxaparin until INR has been 2 to 3 for two consecutive days. This should be discussed with the surgeon. Always monitor CBC to detect heparin-induced thrombocytopenia while the patient is on a heparin product. Example (assumes no significant postoperative bleeding): Preop Days Warfarin Dose Enoxaparin Dose 1 0 0 2 0 1 mg/kg q12h 3 0 1 mg/kg q12h 4 0 1 mg/kg q12h 5 0 0.5 mg/kg at 8 AM Morning Surgery 0 0 Postop days 0 0 1 5 mg 1 mg/kg q12h 2 5 mg 1 mg/kg q12h 3 Per INR 1 mg/kg q12h 4 Per INR 1 mg/kg q12h 5 Per INR Until INR Therapeutic ≥ 2 days : 8

Lumbar puncture (including epidural injections) should be avoided at least 24 hours after therapeutic doses of enoxaparin are given. Otherwise, there is the risk of a spinal epidural hematoma. Warfarin interactions: Interactions with drugs Anticoagulant effect increased Acetaminophen Miscellaneous antibiotics Amiodarone Nonsteroidal anti-inflammatory drugs Androgens Oxyphenbutazone Cimetidine Phenylbutazone Ciprofloxacin Propafenone Clofibrate Salicylates Disulfiram Simvastatin Erythromycin Sulfinpyrazone Fluconazole Trimethoprim-sulfamethoxazole Anticoagulant effect decreased: Antithyroid drugs Barbiturates Carbamazepine Cholestyramine Clarithromycin

Ketoconazole Isoniazid Tramadole Thyroid hormones Lovastatin Metronidazole Tamosifen

Dichlorphenazine Dicloxacillin Glutethimide Rifampin Sucralfate

Variable: Phenytoin Food interactions: Spinach, broccoli, turnip greens have high vitamin K content Interactions with herbal medications: St John’s wort, ginseng and garlic cause resistance to warfarin. Gingko increases risk of bleeding DIRECT THROMBIN INHIBITORS These act independently of antithrombin and are effective against fibrin-bound thrombin. All are given intravenously. There is no means of rapidly reversing their activity. Monitoring can be done using the activated partial thromboplastin time. Recombinant Hirudin (e.g. Lepirudin and desirudin) Half-life 120 minutes. Excreted by kidney. Immunogenic. Fatal anaphylaxis has been reported, particularly on repeat administration of the drug. It confers a greater risk of bleeding than argatroban. Bivalrudin Half-life 25 minutes. Excreted by kidney. liver and other sites

9

Argatroban Half-life 45 minutes. Excreted by liver. Not immunogenic

Oral agents Ximelagatran appeared to be a promising agent, as it required no monitoring and had no food or drug interactions. It was never approved by the FDA because of hepatic side effects. A similar agent, dobigatran, appears to have a very low incidence of liver toxicity according to early reports.15 Another drug, rivaroxaban, was found to be superior to Ximelagatran in preventing thromboembolism after hip or knee arthroplasty.18,19

References: 1. Arepally GM and Ortel TL Heparin-induced thrombocytopenia.s New Engl J Med 2006;355:809 2. Warkentin TEs. Heparin-induced thrombocytopenia: diagnosis and management. Circulation 2004;110:454 3. Jaffer AK. Issues in anticoagulant therapy: recent trials start to answer tough questions.Cleveland Clinic J Med 2005;72:157 4. Menajovsky LB and Spandorfer J. Benefits of more aggressive VTE prophylaxis in hospitalized patients. Cleveland Clinic J Med 2003; 71:947 5. Jaffer et al. When patients on warfarin need surgery. Cleveland Clinic J Med 2003; 70:973 6. Hirsh J et al. American Heart Association/American College of Cardiology Foundation Guide to Warfarin Therapy. Circulation 2003;107:1692 7. Schulman S. Care of patients receiving long-term anticoagulant therapy. New Engl J Med 2003;349:675 8. Kovacs MJ et al. Comparison of 10-mg and 5-mg Warfarin Initiation Nomograms Together with LowMolecular-Weight Heparin for Outpatient Treatment of Acute Venous Thromboembolism: A Randomized, Double-Blind, Controlled Trial. Ann Int Med 2003;138:714 9. Daneschvar HL and Daw H. An elderly woman with leg swelling and pain. Cleveland Clinic J Med 2005;72:353 10. Di Nisio M et al. Direct thrombin inhibitors. New Engl J Med 2005;353:1028 11. ibid 353:2827 (correction) 12. Fondaparinux. Medical Letter 2002;44:43 13. Warkentin TE . Focus on research: drug-induced immune-mediated thrombocyropenia. New Engl J Med 2007;356:891 14. Francis CW. Prophylaxis for thromboembolism in hospitalized medical patients. New Engl J Med 2007;356:1438 15. Ezekowitz MD et al. Dobigatran with or without concomitant aspirin compared with warfarin alone in patients with atrial fibrillation (PETRO study). Am J Card 2007; 100:1419-1426 16. Douketis JD. Perioperative management of warfarin therapy: to bridge or no to bridge, that is the question. Mayo Clin Proceedings 2008; 83:628-629 17. Lauer et al. Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes. Circulation.; 2001;104:2772-2777. 18. Eriksson BI et al, Rivaroxaban versus enoxaparin after total hip arthroplasty. New Engl J Med 2008;358:2765-2775

10

19. Lassen MR et al, Rivaroxaban versus enoxaparin after total knee arthroplasty. New Engl J Med 2008;358:2776-2787 20. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation. 1998;97: 251–256. 21. Antman EM et al. 2007 Focused update of the 2004 ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction J Am Coll Cardiol 2008; 51:210-247

11